The past decade has witnessed the discovery of forty or more peptides localized in neurons of mammalian brain. Many cases of peptides coexisting in the same neuron with classical transmitters have been described. Our laboratory is investigating the functional significance of coexisting peptides and transmitters in the central nervous system, using behavioral tools. Our approach involves cannulating the postsynaptic nucleus containing the nerve terminals and postsynaptic receptors of pathways in which neuropeptides and neurotransmitters coexist. Behavioral actions of the transmitter, the peptide, and combinations of transmitters and peptide(s), microinjected directly into the postsynaptic site, and then evaluated to test for potential interactions between the behavioral effects of the transmitter and the peptide(s). A) We previously showed that cholecystokinin (CCK) potential dopamine-induced hyperlocomotion in the nucleus accumbens, where CCK and dopamine coexist. This year, antagonists of CCK were analyzed for their pharmacological specificity in blocking the CCK modulation of dopaminergic function. Both microinjections into the nucleus accumbens and intrapertitoneal systemic injections of proglumide and benzotript specifically blocked the ability of CCK to potentiate dopamine-induced hyperlocomotion in the nucleu accumbens. This finding demonstrates that a clinically useful route of administration of a CCK antagonist can block central CCK function, suggesting that CCK antagonists may be novel antipsychotic agents in reducing dopaminergic function in the mesolimbic pathway. B) Substance P (SP), corticotropin releasing factor (CRF) and acetylcholinesterase (Ach E) were found to coexist in dorsolateral tegmental neurons projecting to the rat prefrontal cortex. The cholinergic agonist, carbachol, microinjected into the prefrontal cortex, induced a profound stereotyped motor behavior resembling "boxing." SP potentiated carbachol-induced "boxing." The functional significance of this triple coexistence, therefore, may be an upregulation by one peptide, and a down regulation by the other peptide, of the function of the primary transmitter.